ZA200109496B

ZA200109496B - 5-phenyl-pyrimidine derivatives.

Info

Publication number: ZA200109496B
Application number: ZA200109496A
Authority: ZA
Inventors: Michael Boes; Thierry Godel; Walter Hunkeler; Heinz Stadler; Guido Galley; Torsten Hoffmann; Patrick Schnider
Original assignee: Hoffmann La Roche
Priority date: 1999-05-31
Filing date: 2001-11-16
Publication date: 2003-02-17
Also published as: HUP0201527A3; AU769265B2; HUP0201527A2; NO321334B1; US6756380B1; MA26794A1; TR200103460T2; TWI263638B; EP1187814B1; NO20015701L; AU5070800A; KR20020003399A; MY136258A; NZ515408A; HK1046411A1; IL146519A0; JO2308B1; BR0011097A; CZ20014273A3; IL146519A

Description

5-Phenyl-pyrimidine derivatives

The present invention relates to compounds of the general formula e (R), (Rn

Rr?

NE

.

NNR R wherein

R' is hydrogen or halogen;

R’ is hydrogen, halogen, lower alkyl or lower alkoxy; rR’ 1s halogen, trifluoromethyl, lower alkoxy or lower alkyl;

R*R* are independently from each other hydrogen or lower alkyl;

R’ is lower alkyl, lower alkoxy, amino, hydroxy, hydroxy-lower alkyl, } -(CHa)a-piperazinyl, optionally substituted by lower alkyl, 0 -(CHz)a-morpholinyl, -(CHz)y,1-imidazolyl, -O-(CHa)a.i-morpholinyl, -O-(CHa:)u41-piperidinyl, lower alkyl-sulfanyl, lower alkyl-sulfonyl, benzylamino, -NH-(CH2)arN(R")z, -(CH2)o-NH-(CH2)an N(R"), -(CH2)an N(R )2, or -O-(CHa) ns N(RY)3, wherein R* is hydrogen or lower alkyl;

R® is hydrogen;

Rand R® or R' and R® may be together with the two carbon ring atoms ~CH=CH-CH=CH-, with the proviso that n for R" is 1; n is independently 0 - 2; and

X is ~C(O)N(R*)- or -N(R*)C(0O)-; and to pharmaceutically acceptable acid addition salts thereof.

Pop/07.03.2000

= WO p0/73278 PCT/EP00/04702 . © 2 -

The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue.

The receptor for substance P is a member of the superfamily of G protein-coupled receptors.

The neuropeptide receptors for substance P (NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are : involved in regulating a number of diverse biological processes.

The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson’s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640 ~ 1645).

Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer’s disease, multiple sclerosis, attenuation of morphine withdrawal, . cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases reviewed in “Tachykinin Receptor and Tachykinin Receptor Antagonists”, J.

Alitofl. PHdtiacol., 13, 23-93, 1993. CT TT

Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).

The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.

In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1- receptor antagonist.

Objects of the present invention are the compounds of formula I and pharma- ceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above- mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.

The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either : depressed mood or the loss of interest or pleasure in all, or nearly all activities.

The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. As used herein, the term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t- butyl and the like.

Preferred lower alkyl groups are groups with 1-4 carbon atoms.

The term “lower alkoxy” denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom. :

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.

Exemplary preferred are compounds, in which X is ~C(O)N(RY)-, wherein RY is methyl and R” is —(CH,) ,-piperazinyl, optionally substituted by methyl, and nis 0 or 1, for example the following compounds: 5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 5-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide or 5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.

Further preferred are compounds, in which X is —=C(O)N(R*")-, wherein R*" is methyl and R is ~O(CH,),-morpholinyl .

An examples of such a compound is 5-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amid.

Preferred are further compounds, in which X is —C(O)N(RY)-, R* is methyl and R™ is -NH(CH3)a+1N(CHa),, -(CH2),-NH(CH:)1+1N(CH3)1 or -O(CH2)a+1N(CH3)2, wherein n is 1 or 2, for example the following compounds: 5-(2-chloro-phenyl)-2-(2-dimethylamino-ethylamino)-pyrimidine-4-carboxylic acid (3,5- bis-trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis- triffuoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-(2-methoxy-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-(4-fluoro-phenyl)-pyrimidine-4-carboxylic acid (3,5- bis-trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-(4-fluoro-2-methyl-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, : 20 5-(2-chloro-phenyl)-2-(3-dimethylamino-propoxy)-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, i 5-(2-chloro-phenyl)-2-(2-dimethylamino-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, : ._ 2-(2.dimethvlamino-ethoxy)-5-o-talyl-pyrimidine-4-carhoxylic acid {3 8-bis- trifluoromethyl-benzyl)-methyl-amide, 2-(3-dimethylamino-propoxy)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-propoxy)-5-(2-methoxy-phenyl)-pyrimidine-4-carboxylic acid (3,5- bis-trifluoromethyl-benzyl)-methyl-amide, 2-(3-dimethylamino-propoxy)-5-(4-fluoro-2-methyl-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethoxy)-5-(4-fluoro-2-methyl-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide or 5-(2-chloro-phenyl)-2-[(2-dimethylamino-ethylamino)-methyl]-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.

Further preferred are compounds, wherein X is -CON(R*), and R*" is methyl and R” is

SCH, for example the following compounds: 2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)- methyl-amide or 5-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide.

Other preferred compounds are those, in which X is —<CON(R*), and R*" is methyl and R* and R®or R' and R® are together with the two carbon ring atoms —-CH=CH-CH=CH-, for example the following compounds: 2-(4-methyl-piperazin-1-yl)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis- : trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5- bis-trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethoxy)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 2-(2-morpholin-4-yl-ethoxy)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide or 2-(3-dimethylamino-propoxy)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide.

Further preferred are compounds, wherein X is -N(R*)C(0)-, RY is lower alkyl and

Ris -(CH,)n-piperazinyl, optionally substituted by lower alkyl, -(CH,),-morpholinyl, -NH-(CH;)n+1N(CH3); or -O-(CH2)a+iN(CHa3)a, for example the following compounds: 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-5-o-tolyl- pyrimidin-4-ylj-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin- 1-yl-5-o-tolyl-pyrimidin-4- yl)-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-5-o0-tolyl-pyrimidin- 4-yl)-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethylamino)-5-o-tolyl- pyrimidin-4-yl}-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethoxy)-5-0-tolyl-pyrimidin- 4-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-{5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yl}-N-methyl-isobutyramide or

"tT WQ,00/73278 PCT/EP00/04702 2-(3,5-bis-trifluoromethyl-phenyl)-N-{5-(2-chloro-phenyl)-2-(2-dimethylamino- ethylamino)-pyrimidin-4-yl]-N-methyl-isobutyramide.

The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises a) reacting a compound of formula i” (R,

R? _- NHR :

A

R® with a compound of formula (RY),

Cl

RY "R* Hi 10 to a compound of formula

RS (R' In 2 4" . oo Re CFORRY RY,

N

N° -

R® wherein R'- R? and n have the significances given above, or b) reacting a compound of formula

. RS (R’ Da

R? 0 = OH

No N

Nw

R® with a compound of formula (rR),

R® RY

AY to give a compound of formula

RS (R' In 2 . - R 0 R*R* (Ry = 0]

NaN R hel 1-2 : - R® wherein R'-R” and n have the significances given above, or ) ¢) modifying one or more substituents R'-R’ within the definitions given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.

In accordance with process variant a) a compound of formula II, for example [5-(2- chloro-phenyl)-2-methylsulfonyl-pyrimidin-4-yl}-methyl-amine is deprotected with

KHMDS (potassium hexamethyldisilazide) in THF at 0° for 1 h and a compound of formula III, for example 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride is added and the mixture is stirred at room temperature. A typical solvent is N,N- dimethylformamide. The desired compound of formula I-1 is obtained in good yields.

Process variant b) describes the reaction of a compound of formula IV with a compound of formula V to a compound of formula I-2. The reaction is carried out in conventional manner, for example in a solvent, such as dichloromethane in presence of

“+ WO,00/73278 PCT/EP00/04702

NEt;, EDCI (N-(3-dimethylaminopropyl)-N’-ethyl carbodiimide hydrochloride) and

HOBT (1-hydroxy-benzotriazole). The mixture is stirred for about 12 hs at room temperature. The desired product is obtained after purification in good yields.

The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids came into consideration.

Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.

The following schemes 1-6 describe the processes for preparation of compounds of formula I in more detail. The starting materials of formulae III, VIII, IX, XII, XIII, XVI,

XVII and XII are known compounds and may be prepared according to methods known in the art.

In the schemes the following abbreviations have been used:

THF tetrahydrofuran

DIPEA N-ethyldiisopropyl-amine

HOBT 1-hydroxy-benzotriazole

EDCI N-(3-dimethylaminopropyl)-N’-ethyl-carbodiimide hydrochloride m-CPBA m-chloroperbenzoic acid

DPPA diphenylphosphorylazide

DMF dimethylformamide

NEt; triethylamine

KHMDS potassium hexamethyldisilazide

Scheme 1

Br O 4 4

R\ R EDCI, HOBT, NEt

AN OH 3 3 + H,N (R )a —————

NN Vii CH,Cl,

X (X=SCH, CH, X

Br O rR? RY 4 4' RY

Br QR R R) NaH, Mel SP "

AN n ——ee NN

NA H DWF x XI

X : (R),

X i” RY), R 2 2 4 . :

R R QRY_R* m-CPBA

Ho Bon XI Xr ON RY), —_—

CH,CI, > N.2N (PPh,)Pd _ dimethoxyethane 1 |-3 (X=SCH,) 1

R? (R), RY Rn

R? ORY RY

R? ORY R* amine RAR RY

EN RY di > AS N n

N n ioxan NR

NeoN | ¥

I A

5=0 }-5 0) 1-4 alcohol

Cs,CO, )

H,0 CH, CN

NaOH RS (R)s

R® ORY R* 6 RY,

R ( AN RY),

N._=N

R? ORY R* Y

N RY, B

A 1-7

NN

OH 1-6

The substituents R' - R® are given above.

A is an amine group, such as amino, piperazinyl, optionally substituted by lower alkyl, morpholinyl, imidazolyl, piperidinyl, benzylamino or NH-(CH2)p N(R), and B is lower alkoxy, -O-(CH3)n+1-morpholinyl, -O-(CH;) a+ -piperidinyl or -0-(CH2)ne i N(R);

Scheme 2 . RS R"),

Br O r . R' ), R? o xX o> R PPh . Pd(OAc), - PPh, ~ 0

NN 2 _—— he R NEt, , DMF NN

SCH, Xill .B. 3

HO" OH SCH, wv !

R® R a — EDCI, HOBT, NEt, g R':

OH R 0 5 R = OH ®), Rr? OR! 4 3 :

Ny 50 = N ? R )n ross

SCH, xv RR xv NSN

SCH, 3

The substituents are given above.

Claims

1. Compounds of the general formula - RE (RY), (RY, . . R? AS Ne : 4 4 NNR R wherein R' is hydrogen or halogen; R? is hydrogen, halogen, lower alkyl or lower alkoxy; R’ is halogen, trifluoromethyl, lower alkoxy or lower alkyl; R*R* are independently from each other hydrogen or lower alkyl; R’ is lower alkyl, lower alkoxy, amino, hydroxy, hydroxy-lower alkyl, -(CHas),-piperazinyl, optionally substituted by lower alkyl, -(CHa)y-morpholinyl, -(CHz),+1-imidazolyl, -O-(CH;)n4+1-morpholinyl, . -O-(CHa)q41-piperidinyl, lower alkyl-sulfanyl, lower alkyl-sulfonyl, benzylamino, a NHC RR 5 (CHL MEA CH mR (CH me NR ror -O-(CH3)pe;N(R* 3, wherein RY is hydrogen or lower alkyl; R® is hydrogen; R* and R® or R' and R® may be together with the two carbon ring atoms ~CH=CH-CH=CH-, with the proviso that n for R' is I; n is independently 0 - 2; and X is ~C(O)N(R*")- or -N(R*)C(0)-; or pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1, wherein X is ~C(O)N(R*)-, RY is methyl and R’is —(CHa,)n-piperazinyl, otionally substituted by methyland nis OQ or 1.

3. A compound according to claim 2, which is 5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4- carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 5-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide or 5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.

4. A compound according to claim 1, in which X is —C(O)N(RY)-, RY is methyl and R® is —O(CH,),-morpholinyl .

5. A compound according to claim 4, which is 5-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amid.

-

6. A compound according to claim 1, in which X is —C(O)N(RY)-, RY is methyl and R’ is -NH(CH3)n+1N(CH3)2, -(CH2)n-NH(CH2)1N(CHs)2 or -O(CH2)niN(CHa)z ] 20 whereinnis1or?2, So

7. A compound according to cdi 6, whien is oo 5-(2-chloro-phenyl)-2-(2-dimethylamino-ethylamino)-pyrimidine-4-carboxylic acid (3,5- bis-trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-(2-methoxy-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-(4-fluoro-phenyl)-pyrimidine-4-carboxylic acid (3,5- bis-trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-(4-fluoro-2-methyl-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,

a —— : -51- PCT/EP00/04702 5-(2-chloro-phenyl)-2-(3-dimethylamino-propoxy)-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 5-(2-chloro-phenyl)-2-(2-dimethylamino-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethoxy)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl- benzyl)-methyl-amide, . 2-(3-dimethylamino-propoxy)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl- benzyl)-methyl-amide, 2-(2-dimethylamino-propoxy)-5-(2-methoxy-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 2-(3-dimethylamino-propoxy)-5-(4-fluoro-2-methyl-phenyl)-pyrimidine-4-carboxylic acid (3,5- bis-trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethoxy)-5-(4-fluoro-2-methyl-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide or 5-(2-chloro-phenyl)-2-[(2-dimethylamino-ethylamino)-methyl]-pyrimidine-4-carboxylic acid (3,5- bis-trifluoromethyl-benzyl)-methyl-amide.

8. A compound according to claim 1, wherein X is -CON(R*"),,R* is methyl and R’ is SCH.

9. A compound in accordance with claim 8, which is 2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl- amide or 5-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-4-carboxylic acid (3,5-bis-

10. A compound according to claim 1, wherein X is -CON (R*"),,R*’ is methyl and R2 and RS or R! and R® are together with the two carbon ring atoms -CH=CH-CH=CH-.

11. A compound in accordance with claim 10, which is 2-(4-methyl-piperazin-1-yl)-5-naphthalen-1-yl-pyrimidine-4-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 2-(2-dimethylamino-ethylamino)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, AMENDED SHEET

© WO-00/73278 PCT/EP00/14702 - my. 2-(2-dimethylamino-ethoxy)-5-naphthalen-1-yl-pyrimidinc-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide, 2-(2-morpholin-4-yl-ethoxy)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide or 2-(3-dimethylamino-propoxy)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis- trifluoromethyl-benzyl)-methyl-amide.

12. A compound according to claim 1, wherein Xis X is ~N(R*)C(0)-, R* is lower alkyl and R’ is -(CH,),-piperazinyl, optionally substituted by lower alkyl, -(CH3)p-morpholinyl, -NH-(CH3);+1N(CH3); or -O-(CH3),+1N(CHa)2.

13. A compound in accordance with claim 12, which is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-5-o-tolyl- pyrimidin-4-yl]-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin-1-yl-5-0-tolyl-pyrimidin-4- yl)-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-5-o-tolyl-pyrimidin- 4-yl)-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethylamino)-5-o-tolyl- pyrimidin-4-yl}-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethoxy)-5-o-tolyl-pyrimidin- 4-yl]-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)- pyrimidin-4-yl]-N-methyl-isobutyramide or 2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-(2-dimethylamino- ethylamino)-pyrimidin-4-yl}-N-methyl-isobutyramide Se

14. A medicament containing one or more compounds as claimed in any oneof claims 1-13 and pharmaceutically acceptable excipients.

15. A medicament according to claim 14 for the treatment of diseases related to the NK-1 receptor antagonists.

16. A process for preparing a compound of formula | as defined in claim 1, which process comprises a) reacting a compound of formula

RS (R' Ja R* AN ANHRY I R® with a compound of formula (RY), 1 Cl RY R* i to a compound of formula 1 RS (R hn 2 a R RORRT (RY, = N NaN 0] he 1-1 RS ? wherein R'- R” and n have the significances given in claim 1, X or b) reacting a compound of formula oe R), R® 0 = OH Na oN Y WY

_ . . . . . RS ee . with a compound of formula

PCT/EP00/04702 : RY, _ RY R* "to give a compound of formula ox. ¢ )a oo R® O pt | 3 °o RR (R Ja = N : Nel B® Y I-2 R® : wherein R'-R® and n have the significances given in claim 1, or ¢) modifying one or more substituents R'-R’ within the definitions given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid : addition salt. oo

17. A compound according to any one of claims 1-13, whenever prepared bya : : - process as claimed in claim 14 or by an equivalent method.

18. The use of a compound in any one of claims 1-13 for the treatment of diseases. TT IY. The Use of a compound in any one of claims 1-13 for the manufacture ofa ~~ = medicament containing one or more compounds of claims 1 — 13 for the treatment of diseases related to the NK-1 receptor. :

20. A substance or composition for use is a method of treatment of diseases related to the NK-1 receptor said substance or composition comprising a compound in any one of claims 1-13 and said method comprising administering said substance or composition.

; . AMENDED SHEET :

-— ; -55- PCT/EPO0/04702

21. The invention as hereinbefore described.

22. A compound according to claim 1, substantially as herein described and illustrated.

23. A medicament according to claim 14, substantially as herein described and illustrated.

24. A process according to claim 16, substantially as herein described and illustrated.

25. Use according to claim 18 or claim 19, substantially as herein described and illustrated.

26. A substance or composition for use in a method of treatment according to claim 21, substantially as herein described and illustrated.

27. A new compound, a new medicament, a new process for preparing a compound, a new use of a compound as defined in any one of claims 1 to 13, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET